The number of people in the US aged 85 or older is expected to increase ~4-fold between 2000 and 2050 (www.census.gov). Aging is associated with a decline decline in the function of most organs including the gastrointestinal (GI) tract. Age-related changes in the GI tract include increased gastroesophageal reflux, irritable bowel syndrome, constipation and fecal incontinence, as well as more subtle dysfunctions such as inability to consume large volumes of food. Together, these changes negatively affect general well-being, quality of life, the ability to maintain independence, and represent a significant health care burden. The mechanisms of GI aging remain obscure. Gut function is governed by a dynamic interaction between the many cell types in the GI tract including epithelial cells, immune cells, smooth muscle cells, neurons and glia, and interstitial cells of Cajal (ICC). Until recently, neuromuscular dysfunction was believed to be the major contributor to age-related GI problems due to degeneration of the enteric nervous system and smooth muscles. However, little is known of age-related changes to ICC, the pacemaker cells of the gut. Here I propose to study ICC loss due to senescence of ICC stem cells as a key mechanism contributing to GI aging. My central hypothesis is that changes in epigenetic regulation of molecular pathways controlling stem cell self- renewal are responsible for ICC stem cell senescence and consequent loss of mature ICC in aging. My specific aim is to test the novel hypothesis that reduced epigenetic control of Wnt expression by polycomb group transcriptional co-repressors underlies ICC stem cell senescence. I will quantify ICC and ICC precursors in gastric muscles from the klotho mouse, a model of premature aging, by flow cytometry. In two established ICC stem cell lines, I will study gene expression and the role of Wnt signaling and its epigenetic control by polycomb proteins using real-time RT-PCR, Western immunoblotting and RNA interference. Results from this project may reveal new therapeutic targets to restore ICC stem cells and improve GI health in aging. Moreover, this study will emphasize the role of adult stem cells in aging, and may provide strategies to target aging phenotypes and improve quality of life in a rapidly expanding population of aged people. PUBLIC HEALTH RELEVANCE: Aging-related gastrointestinal disorders including constipation, fecal incontinence, gastroesophageal reflux and reduced food intake occur frequently in the elderly and constitute a significant healthcare burden. Here I propose to study senescence of stem cells for interstitial cells of Cajal, a cell type critical for gastrointestinal motility, as a mechanism of gastrointestinal aging. The results of this study may uncover new tools to restore gastrointestinal function in aged individuals and may lead to new therapies to slow or manage general effects of aging.